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Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction

Insights From PARAGON-HF
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.119.044491Circulation. 2020;141:338–351

Abstract

Background:

Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men.

Methods:

In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes.

Results:

Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro–B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59–0.90) in women and 1.03 (95% CI, 0.84–1.25) in men (P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men.

Conclusions:

As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding.

Clinical Trial Registration:

https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

Clinical Perspective

What Is New?

  • Women represent approximately a quarter of people with heart failure and reduced ejection fraction and more than half of those with heart failure and preserved ejection fraction.

  • There are multiple effective drug and device therapies for heart failure and reduced ejection fraction, but none approved for heart failure and preserved ejection fraction; thus, there is a greater heart failure therapeutic deficit in women compared with men.

  • In the PARAGON-HF trial (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), sex and left ventricular ejection fraction appeared to modify the effect of sacubitril-valsartan versus valsartan on the primary outcome (total heart failure hospitalizations and cardiovascular death), with a more favorable treatment effect in women than in men (rate ratio, 0.73 [95% CI, 0.59–0.90] in women; 1.03 [95% CI, 0.84–1.25] in men; P interaction = 0.017).

What Are the Clinical Implications?

  • Whereas the apparent sex-related modification of the effect of sacubitril-valsartan has several potential explanations, the present study does not provide a definite mechanistic basis for this finding.

  • Our findings raise the possibility that the effects of pharmacologic treatments for heart failure and preserved ejection fraction may differ between men and women.

  • This hypothesis should be investigated further, given the therapeutic deficit in this heart failure phenotype in general and particularly in women.

Introduction

Editorial, see p 362

Healthy women, on average, have higher a left ventricular ejection fraction (LVEF) than men and the pattern of left ventricular remodeling seen in response to increased afterload and with aging differs between women and men.1–6 Among patients with heart failure (HF), women are less likely than men to have a markedly reduced LVEF (ie, ≤40%).1–6 Whereas women represent approximately a quarter of people with HF and reduced ejection fraction (HFrEF), they account for over half of those with HF and preserved ejection fraction (HFpEF).1–6 Although there are multiple effective drug and device therapies for HFrEF, there are none with regulatory approval for the treatment of HFpEF and guidelines largely focus on management of hypertension and volume overload and treatment of concomitant comorbidities such as atrial fibrillation.7,8 In addition, the 2017 update of the American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines gave a Class IIb Level B-R recommendation for an aldosterone receptor antagonist in selected patients with HFpEF.8 For this and other reasons, there is a greater HF therapeutic deficit in women compared with men.1,5,6

In the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), the effects of sacubitril-valsartan were compared with those of valsartan, and the primary outcome was a composite of HF hospitalization (first and repeat) and cardiovascular death.9–11 Among the 4796 participants analyzed (52% women), there were fewer primary endpoints in the sacubitril-valsartan group compared with the valsartan group, although the difference was of borderline statistical significance (894 versus 1009 primary events; rate ratio, 0.87 [95% CI, 0.75–1.01]; P=0.059). In the PARAGON-HF trial, there were 12 prespecified subgroup analyses.11 Of these, only sex and LVEF appeared to modify the effect of sacubitril-valsartan versus valsartan on the primary composite outcome, with a more favorable treatment effect in women than in men. In view of the potential importance of this finding, we defined, in detail, the differences between women and men in the PARAGON-HF trial and further investigated the interaction between sex and the effect of treatment.

Methods

The design and primary results of the PARAGON-HF trial have been described previously.9–11 The ethics committees of each of the participating institutions approved the protocol, and all patients gave written, informed consent. Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Study Patients

Eligibility for the study included New York Heart Association (NYHA) Class II, III, or IV symptoms, an ejection fraction of 45% or higher at or within 6 months of screening, an elevated natriuretic peptide level, evidence of structural heart disease, and diuretic therapy. The natriuretic peptide level threshold for inclusion varied according to whether there had been a recent hospitalization for HF and the presence of atrial fibrillation or flutter. The main exclusion criteria included any previous echocardiographic measurement of LVEF <40%; recent acute coronary syndrome, cardiac surgery, or percutaneous coronary intervention; acute decompensated HF at the time of screening; intolerance to either study drug (or similar classes) or a history of angioedema; systolic blood pressure >180 mm Hg or <110 mm Hg; estimated glomerular filtration rate <30 mL/min/1.73 m2; and serum potassium level >5.2 mmol/L.

Trial Procedures

All patients initially received valsartan at half the target dose (single-blind run-in period) and then sacubitril-valsartan at half the target dose (single-blind run-in period). If this dose was tolerated, patients were then randomized to treatment with either sacubitril-valsartan or valsartan in a 1:1 fashion. The target doses were sacubitril-valsartan 97 mg/103 mg twice daily or 160 mg of valsartan twice daily. The 103 mg of valsartan in sacubitril-valsartan is equivalent to 160 mg of the standard valsartan formulation.

Trial Outcomes

The primary outcome was a composite of first and recurrent hospitalizations for HF and death from cardiovascular causes. Secondary outcomes were change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS12) from baseline to 8 months (with a score from 0 to 100, higher scores corresponding to fewer symptoms and limitations), change in NYHA class from baseline to 8 months, time to the first occurrence of a decline in renal function (defined as a reduction of 50% or more in estimated glomerular filtration rate, development of end-stage renal disease, or death caused by renal failure), and time to death from any cause. Safety outcomes included hypotension (defined as a systolic blood pressure <100 mm Hg), elevation of serum creatinine, elevation of serum potassium, and angioedema.

Statistical Analysis

The trial was designed to recruit 4600 patients and continue until 1847 primary events occurred. Between 2014 and 2016, 10 359 patients in 43 countries were screened and a total of 4796 patients were finally included. Patients were analyzed according to sex (baseline characteristics were compared using t tests, Wilcoxon rank-sum tests, and χ2 tests, where appropriate). The primary composite outcome, its components, change in KCCQ-CSS from baseline to 8 months, change in NYHA class from baseline to 8 months, and death from any cause were analyzed, as was safety. An additional expanded primary composite outcome, which included urgent HF visits, was also analyzed. For both sexes, the effect of sacubitril-valsartan compared with valsartan on the primary composite outcome, its components, and the expanded primary composite outcome was examined using the semiparametric proportional rates method of Lin et al13 stratified according to region. The cumulative recurrent events were displayed using Nelson-Aalen cumulative hazard curves and cumulative first events were displayed using Kaplan-Meier curves. The primary composite outcome and its components were also analyzed using Cox regression for time to first event, as were the renal composite outcome and death from any cause. Changes from baseline to 8 months in KCCQ-CSS, systolic blood pressure, and pulse pressure, and from baseline to 1 year in NT-proBNP (N-terminal pro–B-type natriuretic peptide) and urinary cyclic guanosine monophosphate (cGMP)/creatinine, were analyzed using a multilevel mixed-effects linear regression model, together with a multilevel mixed-effects logistic regression model for a 5-point or greater change in KCCQ-CSS. Change from baseline to 8 months in NYHA class was analyzed using a multilevel mixed-effects logistic regression model. The interaction between sex and treatment on each outcome was assessed in each respective statistical test and in a logistic regression model for the safety outcomes. Models were adjusted for differences in baseline characteristics between women and men (age, heart rate, systolic blood pressure, body mass index, smoking status, NT-proBNP [log], estimated glomerular filtration rate, NYHA class, LVEF, previous HF hospitalization, myocardial infarction, diabetes mellitus, and atrial fibrillation); analyses were either stratified (prespecified primary and secondary outcomes) or adjusted for geographical region. A fractional polynomial was constructed using LVEF and entered into the model as an interaction term with treatment. The results of the interaction were displayed graphically using the mfpi command in STATA. The effect of sacubitril-valsartan compared with that of valsartan was modeled over the spectrum of LVEF in women and men separately. All analyses were conducted using STATA version 16 (StataCorp LLC; College Station, TX). P value <0.05 was considered statistically significant.

Results

Patient Characteristics

Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older than men and had more obesity, a lower median NT-proBNP level, and a lower mean estimated glomerular filtration rate than men (Table 1). The distribution of LVEF in women and men is shown in Figure I in the online-only Data Supplement. The median LVEF in women was 60% and in men it was 55%. Women had a worse NYHA class distribution, worse KCCQ-CSS (and overall summary score), and more symptoms of HF. Women were much less likely than men to be a current or past smoker and had a lower prevalence of coronary heart disease, diabetes mellitus, and chronic obstructive pulmonary disease. Women were significantly less likely than men to be treated with a nitrate, a statin, antiplatelet therapy, an anticoagulant, or a mineralocorticoid receptor antagonist. Baseline characteristics were balanced between treatment groups in both women and men (Tables I and II in the online-only Data Supplement).

Table 1. Baseline Characteristics of Women and Men in the PARAGON-HF Trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction)

Women (n=2479)Men (n=2317)P Value
Age, y73.6±8.071.8±8.7<0.001
Age category, y<0.001
 50–59143 (5.8)232 (10.0)
 60–69562 (22.7)676 (29.2)
 70–791168 (47.1)942 (40.7)
 ≥80606 (24.4)467 (20.2)
Region0.003
 Asia–Pacific and other379 (15.3)383 (16.5)
 Central Europe885 (35.7)830 (35.8)
 Latin America222 (9.0)148 (6.4)
 North America264 (10.6)295 (12.7)
 Western Europe729 (29.4)661 (28.5)
Race<0.001
 Asian287 (11.6)320 (13.8)
 Black61 (2.5)41 (1.8)
 Other124 (5.0)56 (2.4)
 White2007 (81.0)1900 (82.0)
Duration of heart failure0.41
 0–3 months417 (16.9)356 (15.4)
 3–6 months319 (12.9)267 (11.5)
 6–12 months309 (12.5)307 (13.3)
 1–2 years340 (13.8)339 (14.7)
 2–5 years508 (20.6)485 (21.0)
 >5 years578 (23.4)559 (24.2)
Systolic blood pressure, mm Hg131±16130±150.04
Diastolic blood pressure, mm Hg74±1174±100.99
Pulse pressure, mm Hg57±1556±140.029
Heart rate, beats/min71±1270±120.047
Left ventricular ejection fraction, %58.9±7.956.0±7.6<0.001
Body mass index, kg/m230.4±5.230.0±4.80.001
Body mass index >30 kg/m21272 (51.3)1082 (46.7)0.001
Waist circumference, cm101.8±14.5107.6±14.7<0.001
 Abnormal*1953 (82.8)1339 (61.6)<0.001
Waist/hip ratio0.93±0.121.00±0.11<0.001
eGFR, mL/min/1.73 m260±1865±20<0.001
eGFR <60 mL/min/1.73 m21320 (53.2)1021 (44.1)<0.001
NT-proBNP, pg/mL836 (446–1601)954 (496–1631)0.002
 In patients with atrial fibrillation1712 (1252–2360)1508 (1124–2210)<0.001
 In patients without atrial fibrillation575 (378–1018)625 (381–1103)0.022
Urinary cGMP/creatinine ratio129±70120±610.013
NYHA functional class<0.001
 I49 (2.0)88 (3.8)
 II1865 (75.3)1841 (79.5)
 III554 (22.4)378 (16.3)
 IV10 (0.4)9 (0.4)
KCCQ
 Clinical summary score70.8 (56.3–83.9)79.2 (64.6–90.6)<0.001
 Overall summary score70.8 (55.7–83.6)77.6 (63.5–88.8)<0.001
Medical history
 Atrial fibrillation725 (29.4)827 (35.8)<0.001
 Any history of atrial fibrillation1280 (51.6)1241 (53.6)0.18
 Angina pectoris664 (26.8)724 (31.2)<0.001
 Myocardial infarction389 (15.7)694 (30.0)<0.001
 Hypertension2392 (96.5)2192 (94.6)0.002
 Diabetes mellitus1001 (40.4)1061 (45.8)<0.001
 Previous heart failure hospitalization1113 (44.9)1193 (51.5)<0.001
 Stroke256 (10.3)252 (10.9)0.53
 Chronic obstructive pulmonary disease286 (11.5)384 (16.6)<0.001
 Cancer228 (9.2)205 (8.9)0.67
 Anemia366 (14.8)341 (14.7)0.96
 Renal disease589 (23.9)635 (27.5)0.004
 Other vascular disease266 (10.8)354 (15.4)<0.001
 Coronary artery bypass grafting172 (6.9)398 (17.2)<0.001
 Percutaneous coronary intervention369 (14.9)608 (26.2)<0.001
 Smoking (current or former)546 (22.2)1308 (56.8)<0.001
 ACE inhibitor intolerance155 (6.3)107 (4.6)0.013
Treatments
 Diuretic2352 (94.9)2233 (96.4)0.011
 Mineralocorticoid receptor antagonist590 (23.8)649 (28.0)<0.001
 ACE inhibitor or ARB at screening2145 (86.5)1994 (86.1)0.64
 β-Blocker1985 (80.1)1836 (79.2)0.47
 Calcium channel blocker861 (34.7)779 (33.6)0.42
 Digoxin248 (10.0)202 (8.7)0.13
 Nitrate308 (12.4)391 (16.9)<0.001
 Statin1503 (60.6)1552 (67.0)<0.001
 Antiplatelet256 (10.3)379 (16.4)<0.001
 Anticoagulant762 (30.7)789 (34.1)0.014
Signs and symptoms
 Dyspnea on effort2316 (93.5)2108 (91.1)0.002
 Paroxysmal nocturnal dyspnea108 (4.4)83 (3.6)0.17
 Orthopnea511 (20.6)375 (16.2)<0.001
 Edema930 (37.6)896 (38.7)0.41
 Rales163 (6.6)182 (7.9)0.086
 Third heart sound57 (2.3)54 (2.3)0.94
 Jugular venous distension321 (13.0)334 (14.6)0.13
 Fatigue1328 (53.6)1109 (48.0)<0.001

Data are presented as mean±SD or median (interquartile range) for continuous measures and number (%) for categorical measures. All drugs are at randomization unless otherwise specified. ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; cGMP, cyclic guanosine monophosphate; eGFR, estimated glomerular filtration rate; KCCQ, Kansas City Cardiomyopathy Questionnaire; NT-proBNP, N-terminal pro–B-type natriuretic peptide; and NYHA, New York Heart Association.

*Defined as >88 centimeters in women and >102 centimeters in men.

†Defined as atrial fibrillation or atrial flutter on screening ECG.

‡Data available for 1195 patients (614 women, 581 men).

Clinical Outcomes: Women Versus Men (Control Group)

Comparison of event rates in the control (valsartan) group showed that women and men had similar rates of the composite of HF hospitalization or death from cardiovascular causes, whether analyzed as total events, including first and recurrent hospitalizations (Figure 1), or as time to first event (Figure II in the online-only Data Supplement). When the components of this composite were analyzed individually, women were observed to have higher rates of HF hospitalization and lower rates of cardiovascular death (and death from any cause) as compared with men (Table 2, Figure 1, and Figure II in the online-only Data Supplement. The proportions of women and men reported to have an improvement in NYHA class between baseline and 8 months was similar, but the proportion of women describing a clinically important increase in KCCQ-CSS over this period was greater than the corresponding proportion in men (Table 2).

Table 2. Outcomes of Women and Men in the PARAGON-HF Trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction)

Women (n=2479)Men (n=2317)Interaction P Value
AllSacubitril-Valsartan (n=1241)Valsartan (n=1238)AllSacubitril-Valsartan (n=1166)Valsartan (n=1151)
Primary composite outcome
 Number of events923391532980503477
 Event rate (95% CI)12.7 (11.9–13.6)10.8 (9.8–11.9)14.7 (13.5–16.0)14.8 (13.9–15.8)15.1 (13.8–16.5)14.6 (13.3-16.0)
 Unadjusted rate ratio (95% CI)*0.73 (0.59–0.90)1.03 (0.84–1.25)0.0168*
 Adjusted rate ratio (95% CI)0.73 (0.60–0.90)1.02 (0.83–1.24)0.0225
Primary composite outcome plus urgent HF visits
 Number of events9644115531034523511
 Event rate (95% CI)13.3 (12.5–14.2)11.3 (10.3–12.5)15.3 (14.1–16.6)15.7 (14.7–16.6)15.7 (14.4–17.1)15.6 (14.3-17.0)
 Unadjusted rate ratio (95% CI)*0.73 (0.60–0.91)1.00 (0.82–1.21)0.0329*
 Adjusted rate ratio (95% CI)0.74 (0.61–0.91)0.99 (0.81–1.20)0.0449
Total hospitalizations for HF
 Number of events738298440749392357
 Event rate (95% CI)10.2 (9.5–11.0)8.2 (7.3–9.2)12.2 (11.1–13.3)11.3 (10.6–12.2)11.8 (10.6–13.0)10.9 (9.8-12.1)
 Unadjusted rate ratio (95% CI)*0.67 (0.53–0.85)1.07 (0.85–1.34)0.0046*
 Adjusted rate ratio (95% CI)0.67 (0.54–0.84)1.06 (0.84–1.34)0.0048
CV death
 Number of events1859392231111120
 Event rate (95% CI)2.6 (2.2–2.9)2.6 (2.1–3.1)2.5 (2.1–3.1)3.5 (3.1–4.0)3.3 (2.8–4.0)3.7 (3.1-4.4)
 Unadjusted hazard ratio (95% CI)*1.02 (0.76–1.36)0.90 (0.70–1.17)0.5763*
 Adjusted hazard ratio (95% CI)1.05 (0.78–1.41)0.88 (0.67–1.14)0.3688
Death from any cause
 Number of events312153159379189190
 Event rate (95% CI)4.3 (3.9–4.8)4.2 (3.6–4.9)4.4 (3.8–5.1)5.7 (5.2–6.3)5.7 (4.9–6.5)5.8 (5.0-6.7)
 Unadjusted hazard ratio (95% CI)*0.96 (0.77–1.20)0.97 (0.80–1.19)0.9040*
 Adjusted hazard ratio (95% CI)0.99 (0.79–1.24)0.95 (0.77–1.17)0.8703
First hospitalization for HF or CV death
 Number of events524239285559287272
 Event rate (95% CI)7.9 (7.3–8.6)7.1 (6.3–8.1)8.8 (7.8–9.8)9.3 (8.5–10.1)9.5 (8.4–10.6)9.1 (8.0-10.2)
 Unadjusted hazard ratio (95% CI)*0.81 (0.68–0.96)1.03 (0.87–1.21)0.0440*
 Adjusted hazard ratio (95% CI)†0.78 (0.65–0.92)1.03 (0.87–1.22)0.0213
First hospitalization for HF
 Number of events417183234421222199
 Event rate (95% CI)6.3 (5.7–7.0)5.5 (4.7–6.3)7.2 (6.3–8.2)7.0 (6.3–7.7)7.3 (6.4–8.4)6.6 (5.8-7.6)
 Unadjusted hazard ratio (95% CI)*0.75 (0.62–0.91)1.08 (0.89–1.31)0.0070*
 Adjusted hazard ratio (95% CI)0.72 (0.59–0.87)1.09 (0.90–1.33)0.0025
Change in NYHA from baseline to 8 months
 Improved, n (%)344 (14.5)193 (16.4)151 (12.7)292 (13.0)154 (13.5)138 (12.4)
 Unchanged, n (%)1817 (76.8)881 (74.9)936 (78.6)1742 (77.4)886 (77.7)856 (77.1)
 Worsened, n (%)206 (8.7)102 (8.7)104 (8.7)217 (9.6)100 (8.8)117 (10.5)
 Unadjusted odds ratio (95% CI)*1.72 (1.07–2.76)1.34 (0.80–2.23)0.4401*
 Adjusted odds ratio (95% CI)1.69 (1.04–2.74)1.37 (0.82–2.29)0.5040
Change in KCCQ clinical summary score from baseline to 8 months
 Change−1.3±0.4−1.6±0.5−1.0±0.5−2.9±0.4−1.5±0.5-4.3±0.5
 Difference−0.6 (−2.1 to 0.8)2.8 (1.3 to 4.3)0.0013* 0.0032
 Increase ≥5 points, n (%)761 (33.3)386 (34.0)375 (32.7)640 (29.2)357 (32.0)283 (26.3)
 Unadjusted odds ratio (95% CI)*§1.09 (0.81–1.46)1.57 (1.14–2.15)0.1080*
 Adjusted odds ratio (95% CI)§1.11 (0.83–1.50)1.55 (1.13–2.13)0.1602
Renal composite outcome
 Number of events481632491732
 Event rate (95% CI)0.7 (0.5–0.9)0.4 (0.3–0.7)0.9 (0.6–1.3)0.7 (0.6–1.0)0.5 (0.3–0.8)1.0 (0.7–1.4)
 Unadjusted hazard ratio (95% CI)*0.49 (0.27–0.89)0.53 (0.29–0.95)0.8956*
 Adjusted hazard ratio (95% CI)0.46 (0.25–0.84)0.47 (0.26–0.86)0.9714
New-onset atrial fibrillation
 Number of events14484601185365
 Event rate (95% CI)2.1 (1.7–2.4)2.4 (1.9–3.0)1.7 (1.3–2.2)1.8 (1.5–2.2)1.6 (1.2–2.1)2.1 (1.6–2.6)
 Unadjusted hazard ratio (95% CI)*1.41 (1.02–1.97)0.79 (0.55–1.13)0.0189*
 Adjusted hazard ratio (95% CI)1.43 (1.02–1.99)0.78 (0.54–1.12)0.0139
Change in NT-proBNP from baseline to 1 year
 Change, pg/mL−114±39−182±55−45±55−133±53−259±732±76
 Difference−137 (−289 to 15)−261 (−468 to −54)0.3573*
0.3764
Change in urinary cGMP/creatinine from baseline to 1 year
 Change−22.4±2.54.7±3.6−49.9±3.6−20.5±2.25.8±3.0-48.7±3.2
 Difference54.6 (44.6 to 64.5)54.5 (45.8 to 63.1)0.9935*
0.9087
Change in systolic blood pressure from baseline to 8 months
 Change, mm Hg1.9±0.3−0.3±0.54.1±0.50.8±0.3−1.4±0.53.1±0.5
 Difference−4.3 (−5.6 to −3.0)−4.6 (−5.9 to −3.3)0.8058*
0.8727
Change in pulse pressure from baseline to 8 months
 Change, mm Hg1.2±0.3−0.3±0.42.6±0.40.6±0.3−0.9±0.42.2±0.4
 Difference−2.9 (−4.0 to −1.8)−3.1 (−4.2 to −2.0)0.8109*
0.9559

Event rate is number of events per 100 person-years. Plus-minus values are means±SE. Unadjusted models for change in New York Heart Association (NYHA) functional class, Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, NT-proBNP (N-terminal pro–B-type natriuretic peptide) level, urinary cyclic guanosine monophosphate (cGMP)/creatinine, systolic blood pressure, and pulse pressure also include the baseline value. CV indicates cardiovascular; and HF, heart failure.

*Model stratified by or adjusted for region.

†Model adjusted for age, heart rate, systolic blood pressure, body mass index, NT-proBNP level (log), estimated glomerular filtration rate, NYHA functional class, left ventricular ejection fraction, previous HF hospitalization, myocardial infarction, diabetes mellitus, smoking, atrial fibrillation (except for time to new-onset atrial fibrillation), and either stratified by or adjusted for region.

‡Odds ratio for improvement vs no improvement.

§Odds ratio for increase ≥5 points.

Figure 1.

Figure 1. Cumulative hazard estimate for the primary composite outcome and total hospitalizations for heart failure (first and repeat) according to sex and treatment in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction). A, Cumulative hazard estimate for the primary composite outcome. B, Cumulative hazard estimate for total hospitalizations for heart failure (HF).

Effect of Sacubitril-Valsartan: Women Versus Men

The rate ratio for the primary outcome with sacubitril-valsartan, compared with valsartan, in women was 0.73 (95% CI, 0.59–0.90) and in men it was 1.03 (95% CI, 0.84–1.25; P interaction = 0.017; Table 2 and Figure 1). Adjustment for the baseline differences between women and men did not change this result (Table 2). An alternative approach to analysis of recurrent events (negative binomial method) gave qualitatively similar findings to the LWYY method (Figure III in the online-only Data Supplement). The composite of HF hospitalization or cardiovascular death, analyzed as time to first event, gave similar findings to the analysis of total events (Table 2 and Figure II in the online-only Data Supplement).

Further examination of the apparent benefit of sacubitril-valsartan over valsartan in women showed that the effect was predominantly related to HF hospitalization, with no discernible reduction in death from cardiovascular causes (or from any cause; Table 2, Figure 1, and Figure II in the online-only Data Supplement). The magnitude of the effect on first and recurrent hospitalizations for HF was substantial, with a 33% (95% CI, 15–47) relative risk reduction in women versus men (P interaction = 0.005). Analysis of first hospitalizations for HF gave similar findings to total (first and recurrent) admissions (Figure II in the online-only Data Supplement).

Examination of the effect of treatment across the range of LVEF studied suggested more benefit from sacubitril-valsartan at a lower LVEF, whether using analysis of total events (Figure 2) or analyzing first events only (Figure IV in the online-only Data Supplement). These fractional polynomial analyses also suggested that the upper threshold at which benefit diminished was higher in women than in men (Figure 2 and Figure IV in the online-only Data Supplement).

Figure 2.

Figure 2. Treatment effect in women and men in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) according to left ventricular ejection fraction. A, Treatment effect on the primary composite outcome in women. B, Treatment effect on the primary composite outcome in men. C, Treatment effect on total hospitalizations for heart failure (HF) in women. D, Treatment effect on total hospitalizations for HF in men. Rate ratios and 95% CIs are shown.

The proportional improvement in NYHA class with sacubitril-valsartan was similar in women and men, whereas the relative improvement in KCCQ-CSS seemed to be less in women than in men (although in this responder analysis, examining patients with a ≥5-point improvement, there was no statistically significant interaction between sex and response to sacubitril-valsartan). When examined as a continuous variable, the sacubitril-valsartan versus valsartan difference in KCCQ-CSS change was also more favorable in men compared with women (P interaction = 0.038, adjusted P interaction = 0.067).

The improvement in renal function with sacubitril-valsartan compared with valsartan was similar in women and men (Table 2).

New-Onset Atrial Fibrillation

The risk of new-onset atrial fibrillation was higher in women treated with sacubitril-valsartan compared with valsartan, whereas the opposite was true for men. Although this resulted in a significant interaction between sex and the effect of treatment, the numbers of events were small.

Other Measures: Change in NT-proBNP, Systolic Blood Pressure and Pulse Pressure, and Urinary cGMP/Creatinine

The reductions from baseline to 8 months in systolic blood pressure and pulse pressure and from baseline to 1 year in NT-proBNP with sacubitril-valsartan as compared with valsartan were similar in men and women (Table 2). The increase from baseline to 1 year in urinary cGMP to creatinine ratio with sacubitril-valsartan treatment was also similar in women and men (Table 2).

Effect of Sacubitril-Valsartan: Safety in Women Versus Men

Hypotension was more common, and increases in creatinine and potassium less common, with sacubitril-valsartan as compared with valsartan (Table 3). The difference in these adverse events of interest between sacubitril-valsartan and valsartan was similar in women and men. There were too few cases of angioedema for meaningful analysis by sex.

Table 3. Tolerability and Adverse Events in Women and Men in the PARAGON-HF Trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction)

Women (n=2479)Men (n=2317)Interaction P Value
AllSacubitril-Valsartan (n=1241)Valsartan (n=1238)AllSacubitril-Valsartan (n=1166)Valsartan (n=1151)
Hypotension317 (12.8)195 (15.7)122 (9.9)320 (13.8)185 (15.9)135 (11.7)0.3796*
0.5045
Elevated serum creatinine, mg/dL
≥2.0181 (7.3)75 (6.0)106 (8.6)408 (17.6)186 (16.0)222 (19.3)0.4070*
0.3638
≥2.558 (2.3)28 (2.3)30 (2.4)148 (6.4)69 (5.9)79 (6.9)0.8181*
0.8860
≥3.022 (0.9)12 (1.0)10 (0.8)56 (2.4)26 (2.2)30 (2.6)0.5118*
0.6355
Elevated serum potassium, mmol/L
>5.5330 (13.3)160 (12.9)170 (13.7)347 (15.0)156 (13.4)191 (16.6)0.2515*
0.1085
>6.086 (3.5)35 (2.8)51 (4.1)90 (3.9)40 (3.4)50 (4.3)0.6491*
0.7087
Angioedema14 (0.6)11 (0.9)3 (0.2)4 (0.2)3 (0.3)1 (0.1)0.8840*
0.6968
Liver-related adverse event143 (5.8)64 (5.2)79 (6.4)186 (8.0)87 (7.5)99 (8.6)0.7200*
0.7360
Target dose1368 (82.6)675 (80.6)693 (84.5)1314 (84.5)665 (83.3)649 (85.7)
Discontinuation for reasons other than death679 (27.4)336 (27.1)343 (27.7)569 (24.6)274 (23.5)295 (25.6)

Data are presented as number (%). Hypotension is defined as systolic blood pressure <100 mm Hg. For creatinine, the multivariable model included baseline creatinine level rather than estimated glomerular filtration rate. For potassium, the multivariable model also included baseline potassium level.

*Model stratified by or adjusted for region.

†Model adjusted for age, heart rate, systolic blood pressure, body mass index, NT-proBNP (N-terminal pro–B-type natriuretic peptide level) (log), estimated glomerular filtration rate, New York Heart Association functional class, left ventricular ejection fraction, previous heart failure hospitalization, myocardial infarction, diabetes mellitus, smoking, atrial fibrillation, and region.

‡Data available for 1976 women (993 on sacubitril-valsartan, 983 on valsartan) and 1940 men (989 on sacubitril-valsartan, 951 on valsartan).

Discussion

More than half of the participants in the PARAGON-HF trial were women, representing one of the largest populations of women with HFpEF ever studied. We found that women and men with HFpEF have distinct clinical profiles and that, compared with valsartan, treatment with sacubitril-valsartan led to a greater reduction in HF hospitalization in women than in men. The difference in the clinical profile between men and women with HFpEF is consistent with previous results, particularly in relation to the lower risk of death and greater severity of symptoms in women.1–6 That we observed a greater treatment effect on HF hospitalization in women than men is more novel, and of some interest, given that HFpEF is the predominant phenotype in women.1–6 The proportion of HFpEF in the population may be even higher than indicated by the characteristics of the participants in the PARAGON-HF trial as, in keeping with trials in general, our patients were younger and had less comorbidity than reported in epidemiologic studies.3,5,6

The major question arising is whether this subgroup finding was attributable to chance or represents a real difference between women and men in response to therapy. A framework for interpretation of treatment heterogeneity in subgroups has been provided by several authors.14–17 Key principles include prespecification of the subgroup of interest, that the subgroup should be of sufficient size, and that a statistical test for interaction is carried out. Each of these conditions was fulfilled in the present study and in a further step, an interaction between sex (along with ejection fraction) and the effect of treatment persisted in a multivariable analysis including all prespecified subgroups.11

Other key considerations are biological plausibility and internal consistency and external validation. In terms of biological plausibility, there are several reasons why women might have a more favorable response to neprilysin inhibition than men. The normal LVEF range is higher in women than in men, reflecting sex-related differences in cardiac remodeling in response to factors including blood pressure and age.3–6,18 For a given LVEF, more women than men may have other evidence of contractile dysfunction.2–6,19,20 If correct, this would mean that more women than men in the present study had mild left ventricular systolic dysfunction. This view is consistent with the apparent benefit of sacubitril-valsartan, a drug clearly effective in patients with left ventricular systolic dysfunction, to a higher LVEF value in women compared with men in the fractional polynomial analyses (Figure 2).

Alternatively, age-related arterial stiffening is more pronounced in women than in men and has been postulated to be a key pathophysiologic factor in HFpEF.21 However, the reduction in pulse pressure and systolic blood pressure with sacubitril-valsartan compared with valsartan was similar in women and men, although pulse pressure is a relatively crude measure of arterial stiffness.22

We confirmed that natriuretic peptide levels are lower in women than in men with HFpEF despite more severe symptoms and known higher left ventricular diastolic and systolic stiffness and filling pressures in women compared with men.2–6,19 However, women have much more visceral obesity than men with HFpEF (as evidenced by waist circumference in the present study) and obesity is associated with lower natriuretic peptide levels. There are also known sex differences in natriuretic peptide biology, with crosstalk between these peptides and sex hormones, possibly leading to a decrease in natriuretic peptide levels after menopause.5,23–28 This potential relative natriuretic peptide deficiency will lead to reduced cGMP–protein kinase G signaling.24–31 Any reduction in cGMP–protein kinase G signaling attributable to a relative natriuretic peptide deficiency may be exacerbated in postmenopausal women by of loss of alternative, estrogen-dependent stimulation of this pathway through endothelial nitric oxide synthase activation and nitric oxide generation.5,24–31 Consequently, by augmenting natriuretic peptides, sacubitril-valsartan may be of greater benefit in women than in men, if women are viewed as having deficient cGMP–protein kinase G signaling.5,24–31 The increase in urinary cGMP/creatinine with sacubitril-valsartan was as large in women as in men. The present trial does not provide direct mechanistic evidence to support this hypothesis.

Neprilysin also degrades other biologically active peptides and it is possible that there could be a sex-related difference in these alternative actions of sacubitril-valsartan. Women may have a greater increase than men in bradykinin production with neprilysin inhibition as they are more likely to develop angioedema than men with both neprilysin and angiotensin-converting enzyme inhibition.32

A much smaller proportion of women compared with men were current or former smokers, which may be relevant, because in a population study, smoking was the variable most strongly associated with plasma neprilysin level.33 However, adjustment for smoking status did not change the apparently greater effect of sacubitril-valsartan in women compared with men.

We also considered whether the precipitants of HF hospitalization, one of which is new-onset atrial fibrillation, might differ between women and men.34 Confirmed new-onset atrial fibrillation was relatively infrequent in the trial and the effect of sacubitril-valsartan on this outcome was less favorable in women than in men. This means that incident atrial fibrillation cannot account for the sex-related difference in the effect of sacubitril-valsartan on HF hospitalization.

There may have been a larger subgroup of patients not responsive to treatment with sacubitril-valsartan among men compared with women in the PARAGON-HF trial (eg, patients with undiagnosed cardiac amyloidosis or genetic hypertrophic cardiomyopathy), although it is unclear whether these conditions are more prevalent in men than women with HFpEF.35

From the point of view of internal consistency, we found that improvements in patient-reported and physician-reported outcomes were not greater with sacubitril-valsartan in women compared with men. Change in KCCQ-CSS showed a more favorable response to sacubitril-valsartan in men than in women. This may reflect the much worse KCCQ-CSS at baseline in women or chance. NYHA class improved to a similar extent in women and men. Whereas there is a relatively weak correlation between functional class and health-related quality of life and risk of hospital admission, it is still somewhat surprising that the sex-related responses to sacubitril-valsartan were directionally different for these outcomes. The improvement in renal function with sacubitril-valsartan over valsartan was similar in women and men. Overall, therefore, sacubitril-valsartan had similar (or greater, in the case of KCCQ-CSS) benefits in men as compared with women, with the exception of reduction in HF hospitalization, which was greater in women.

In terms of external validation, sex seems to modify response to some treatments in patients with HF. In HFrEF, women appear to obtain more benefit from cardiac resynchronization therapy but less benefit from digoxin.36,37 In HFpEF, sex-specific spline analysis examining the effect of spironolactone across the range of LVEF studied in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) showed that women appeared to benefit across the whole LVEF spectrum, whereas in men, there was only benefit at a lower ejection fraction.38 Unpublished data from the CHARM-Preserved trial (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) report the same pattern (Figure V in the online-only Data Supplement).39 Whereas these examples support the possibility of sex as a modifier of treatment effect, no such interaction was found for sacubitril-valsartan compared with enalapril in patients with HFrEF in the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), suggesting that any modification of the effect of this treatment by sex is only apparent at higher ejection fractions.40 However, direct comparison of PARADIGM-HF and PARAGON-HF is not straightforward as the comparator therapy in the former trial was enalapril and there is less evidence for benefit of angiotensin-converting enzyme inhibitors compared with angiotensin receptor blockers in women, and the comparator therapy in the PARAGON-HF trial was an angiotensin receptor blocker.39,41 The possible discrepancy in sex differences in treatment response by type of HF (HFpEF versus HFrEF) also seems to be the case for mineralocorticoid receptor antagonists when the TOPCAT findings are compared with those of the HFrEF trials using mineralocorticoid receptor antagonists and for candesartan (CHARM reduced LVEF trials compared with CHARM-Preserved).39,42

PARAGON-HF was an active-controlled trial and, therefore, the possible benefit of sacubitril-valsartan over valsartan in women could reflect lower efficacy of valsartan in women compared with men, though this is not supported by published analyses of trials using angiotensin receptor blockers in HFrEF.39,41

It is unlikely that a greater degree of neprilysin inhibition or angiotensin receptor blockade in women might explain the apparent difference between women and men in response to sacubitril-valsartan.43 Women did not achieve a higher target dose of sacubitril-valsartan than men and did not have a lower treatment discontinuation rate. The pharmacokinetics of sacubitril-valsartan and its metabolites do not differ in women versus men.44 The reduction in blood pressure and NT-proBNP and increase in urinary cGMP was similar in women and men. Collectively, this information makes it unlikely that a greater effective dose leading to a greater neprilysin inhibition or angiotensin receptor blockade could account for the difference between women and men with respect to HF hospitalization.

As with any study of this type, there are some limitations. We do not have information on more sensitive measures of left ventricular systolic function than ejection fraction. We do not have information on cardiac and other biomarkers, including neprilysin levels or sex hormones, except for NT-proBNP and cGMP.

As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of HF hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding.

Footnotes

*Drs McMurray and Jackson contributed equally.

Sources of Funding, see page 349

https://www.ahajournals.org/journal/circ

Guest Editor for this article was Eileen Hsich, MD.

Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.

The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.119.044491.

John J.V. McMurray, MD, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK. Email

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